Foot ulcers are one of the leading causes of hospitalization for people with diabetes in the developed world and a major morbidity associated with diabetes leading to pain, suffering, and a poor quality of life for patients. 25.8 million patients with diabetes in US alone develop foot ulcers at some point in their lives, costing approximately 25 billion dollars in care annually and accounting for 67% of all lower extremity amputations in the US. Bacterial infection has been long recognized as a major impediment to wound healing in diabetic ulcers. A shift in the microbiome toward pathogenic bacteria, such as Pseudomonas aeruginosa occurs in diabetic ulcers and correlates with a poor healing prognosis. The underlying reasons for the inability of diabetic wounds to fight off bacterial infection and the reasons for the microbiome shift toward pathogenic bacteria remain poorly understood. Based on our preliminary data, our central hypothesis is that inadequate neutrophil infiltration early after injury in diabetic wound-- due to impaired neutrophil chemotactic response through the formylated peptide receptor (FPR) -- leads to reduced TLR signaling, reduced inflammatory responses, and reduced pathogen-specific AMP expression, rendering diabetic wound vulnerable to infection with pathogenic bacteria, which further exacerbate diabetic wound, driving it toward hyper-inflammatory and chronic state. In this proposal, we will: (Aim 1) determine the molecular mechanisms that underlie the impaired neutrophil response in diabetic wound; (Aim 2) assess the adverse impact of delayed neutrophil response on signaling through pattern recognition receptors (PRRs); and (Aim 3) assess the adverse impact of delayed neutrophil response on antimicrobial peptides (AMPs) productions, particularly the pathogen-specific AMPs that render diabetic wounds vulnerable to colonization and microbiome shift toward Pseudomonas aeruginosa. We will also evaluate the therapeutic potential of pro-inflammatory chemokines and Toll-like receptor ligands to restore antimicrobial defenses and stimulate healing by jumpstarting the neutrophil response in diabetic wounds early after injury.